The present invention concerns pharmaceutical combination preparations containing erythropoietin and iron preparations. The preparations are used particularly to optimize erythropoiesis for the treatment of diseases in which it is intended to stimulate the formation of erythrocytes.
The subject matter of the present invention is a pharmaceutical combination preparation comprising 250-20,000 U of an erythropoietin preparation and 1-40 mg of an equivalent amount of iron ions of a physiologically compatible iron preparation in which the erythropoietin preparation and the iron preparation can be present in separate forms of administration or in a uniform administrative form.
It is known that anaemia and in particular the anaemia of haemodialysis patients caused by transfusion can be treated with recombinant erythropoietin (rhEPO). Anaemia in chronic diseases is worldwide the second most frequent form of anaemia.
A reduced new production of erythrocytes is in the foreground of anaemias that are caused by reduced erythropoiesis in the bone marrow or by disturbances of iron re-utilization. When the new formation of erythrocytes declines daily by 1%, anaemia cannot be clinically diagnosed until after 1-3 weeks. The daily iron requirement for a normal erythropoiesis is 25 mg. Of this only about 1 mg is derived from the food, the main requirement is normally met by re-utilization of the haemoglobin iron after the degradation of aged erythrocytes. The release of iron from the reticular cells is greatly reduced in chronic diseases. The iron is retained in the reticuloendothelial system and is no longer available for erythropoiesis. One therefore also speaks of an xe2x80x9cinner iron deficiencyxe2x80x9d in which normal compensation mechanisms are incompletely triggered. A reticulocytopenia and an absence of a hyperplasia of the erythropoiesis that would be needed to compensate for the anaemia are typical. A reduced erythropoietin secretion or activity may also be an additional pathogenetic factor. A significant change in iron metabolism is for example the absence of a compensatory increase in transferrin formation. The underlying disorder is therefore the lack of iron release from the iron stores (in the reticuloendothelial cells) into the plasma (and thus also into the erythron) as a result of which the normal compensation mechanisms are not triggered. The administration of recombinant erythropoietin is utilized therapeutically to significantly increase the number of erythrocytes.
In clinical chemistry the concentration of serum ferritin is determined to diagnose anaemia and disorders of iron metabolism. If a real iron deficiency occurs in addition to the anaemia of chronic diseases then there is no increase in ferritin (it usually remains below 90-95 ng/ml). If at the same time there are clinical signs of infection, inflammation or malignant disease, this value indicates a combination of iron deficiency and anaemia accompanied by a chronic disease. Since in these diseases the serum ferritin can also react in the sense of an acute phase protein, the erythrocyte ferritin can be utilized better diagnostically.
The total body iron is ca. 3.5 g in men and 2.5 g in women. Iron is actively metabolised and present in storage compartments. In the active pool of a man an average of 2100 mg is present in haemoglobin, 200 mg in myoglobin, 150 mg in enzymes of the tissue (haem and non-haem) and 3 mg in the iron transport compartment. Iron is stored intracellularly in the tissue as ferritin (700 mg) and as haemosiderin (300 mg).
The bioavailability of the iron can be pathophysiologically disturbed resulting in a reduced iron absorption in the body. Of the approximately 10 mg that is daily available through the diet an adult only absorbs about 1 mg. In iron deficiency the absorption increases, but seldom above 5-6 mg, if no additional iron is supplied. The exact mechanism for the absorption of iron has not been elucidated. The mucosal cells of the small intestine play a decisive role in the regulation. The most important signal for the mucosa appears to be the total iron content of the body. It has been shown that the serum ferritin concentration correlates inversely with the amount of absorbed iron.
The iron is transferred from the intestinal mucosal cells to transferrin. This iron transport protein has two iron binding sites. It is synthesized in the liver. Hence there is a mechanism whereby iron is received by cells (e.g. mucosa of the small intestine, macrophages) and transferred to specific membrane receptors of erythrocytes, placental cells or liver cells. The transferrin-iron-receptor complex reaches the inside of the erythrocyte precursor cells by endocytosis where the iron is passed onto the mitochondria. Here haem is formed from iron and protoporphyrin.
Iron that is not required for erythropoiesis is transferred by transferrin into two types of storage pool. Ferritin is the most important store. This is a heterogeneous family of proteins which surround an iron core. It is soluble and represents the active storage form in the liver (hepatocytes), bone marrow, spleen (macrophages), erythrocytes and in the serum ( about 100 ng/ml). The tissue ferritin pool is very labile and is rapidly available when iron is required. Circulating serum ferritin is derived from the reticuloendothelial system and its circulating concentration parallels that of the total body iron (each ng/ml corresponds to 8 mg iron store).
In the case of haemodialysis patients it has turned out that the iron requirement of patients treated with rhEPO is quite considerable. As a rule an additional iron therapy is usually carried out on these patients since EPO can only develop an optimal action when the corresponding iron stores in the body are as full as possible. Hitherto high doses of iron preparations have been commonly administered to fill up the iron stores as much as possible. However, excessive doses of iron preparations can also lead to undesired side-effects in the patients. In particular the intravenous administration of iron preparations is not physiologically safe due to the extreme toxicity of iron ions. The use of certain iron preparations is usually warned against for patients with known allergic reactions e.g. for asthmatics. It is possible to assess the fill status of the iron stores by determining the protein ferritin and by determining the transferrin saturation (M. Wick, W. Pingerra, P. Lehmann xe2x80x9cEisen-stoffwechsel, Diagnose und Therapie der Anxc3xa4mienxe2x80x9d, pages 5-14, 38-55, 65-80, 94-98; third extended edition, September 1996, Springer publishers Wien, N.Y.) whereby the transferrin saturation represents the flow of iron from the depots to the bone marrow whereas the serum ferritin value is a measure for stored iron.
The iron stores are considered to be xe2x80x9cfullxe2x80x9d when the serum ferritin is  less than 150 xcexcg/l and a transferrin saturation of 20% is present. P. Grxc3xctzmacher et al. describe in Clinical Nephrology, Vol. 38, No. 1, 1992, p. 92-97 that under these conditions one can assume a maximum response to EPO therapy.
In the iron therapy of EPO-treated dialysis patients one currently refers to a xe2x80x9ccorrection phasexe2x80x9d and a xe2x80x9cmaintenance phasexe2x80x9d. In the correction phase the highest possible doses of iron preparations are administered in order to fill up the iron stores as rapidly as possible. In this case suitable iron preparations are expediently administered as an intravenous bolus injection. In the maintenance phase the iron stores are then kept filled with low doses of iron. Suitable iron preparations are no longer administered in this phase as a rapid bolus injection but in the form of conventional infusion preparations or by oral administration.
The iron requirement of a haemodialysis patient treated with rhEPO can be quite considerable in the correction as well as in the maintenance phase. 150 mg iron is required to synthesize 1 g/dl haemoglobin in the correction phase that either has to be covered by endogenous iron stores or has to be supplied exogenously. The iron requirement is also increased in the maintenance phase since small losses of blood occur in haemodialysis patients with every treatment. The iron loss is estimated to be about 1000 mg iron (3 mg/day) over a period of one year. In the long term such a loss can only be compensated exogenously. In principle oral and intravenous forms of administration are available for this.
Since the oral iron absorption is only about 1 mg/day and under extreme loading (with an oral administration of about 300 mg Fe (III)/day) is less than 3 mg/day, an intravenous administration of relatively large amounts of iron is increasingly preferred. On the German pharmaceutical market two iron preparations are at present available that can be administered intravenously. These are the drugs xe2x80x9cFerriecitxe2x80x9d and xe2x80x9cFerrum Vitisxe2x80x9d. Ferriecit is an iron (3) gluconate complex whereas Ferrum Vitis is an iron (3) hydroxide saccharate complex.
The diverse problems of a high-dose, long-term oral iron therapy can be relatively simply circumvented by the intravenous subcutaneous administration of physiologically compatible iron(III) salts during the haemodialysis treatment since in this case there is a safe intravenous subcutaneous access and the injection can be carried out without further stress to the patient. In recent years this procedure has become more and more wide-spread since one assumed that the preparations xe2x80x9cFerrlecitxe2x80x9d and xe2x80x9cFerrum Vitisxe2x80x9d are forms of administration that are relatively free of side effects. However, side effects in connection with the Ferrlecit therapy in autologous blood transfusion have now been reported and the indication for parenteral Ferrlecit therapy has been considerably restricted. Attention has been called to the possibility of circulatory reactions including even collapse as well as to the possible occurrence of anaphylactic reactions. Furthermore the maximum permissible daily dose has been prescribed as two ampoules of 5 ml corresponding to 125 mg iron.
Hence the intravenous administration of both iron preparations is not trivial since side effects may occur when the two drugs are administered, particularly when relatively large amounts have to be injected relatively rapidly. Moreover the intravenous administration of the iron preparations can cause problems even including acute phase reactions if the iron dose is too high or the dose is not optimally matched with the EPO dose.
Obviously the high iron dosages that have to be administered to EPO-treated dialysis patients are disadvantageous. The risk of a myocaridal infarction increases and there is also a significant increase in the risk of developing an iron cirrhosis. Within the framework of treating dialysis patients an adequate supply of iron as well as a suitable method for determining the concentration of iron in body fluids to identify a possible iron deficiency is of considerable therapeutic utility since an inadequate iron availability is one of the main causes of an inadequate action of EPO or of an EPO resistance.
An excessive dosage of preparations containing iron can also lead to iron poisoning. Elemental iron has a toxic effect on the gastrointestinal tract, the cardiovascular and the central nervous system. The oral lethal dose of elemental iron varies between 200 and mg/kg. The most frequently used iron tablets are ferrosulfate (contains about 20% elemental iron), ferrofumarate (contains about 30% elemental iron) or ferrogluconate (contains about 10% elemental iron).
There are four typical stages of iron poisoning: stage I (within the first 6 hours after poisoning): vomiting, diarrhoea, hyperirritability, abdominal pain, fits, apathy and coma can occur. Irritations of the gastrointestinal mucosa can lead to a haemorrhagic gastritis. When there are high serum iron levels tachypnoea, tachycardia, hypotension, shock, coma and metabolic acidosis can occur. Stage II (within the first 10-14 hours after poisoning): During a latency period which can last up to 24 hours an apparent improvement occurs. Stage III (12-48 hours after poisoning): shock, hypoperfusion and hypoglycaemia occur. The level of serum iron can be normal. Liver damage with increased GPT, fever, leucocytosis, coagulation disorders, T-inversion in the ECG, disturbances of orientation, restlessness, apathy, tendency to fits, coma, shock, acidosis and death can occur. Stage IV (2-5 weeks later): possible complications by a pylorus, antrum or another intestinal obstruction, a liver cirrhosis or damage of the central nervous system may be in the foreground.
The object of the invention was to provide a combination preparation of an erythropoietin preparation and an iron preparation which contains an optimally balanced amount of EPO and iron ions for the treatment of disturbances of iron metabolism. In particular it should be possible to avoid the above-mentioned risks, especially the acute phase reactions with the aid of these combination preparations. Furthermore an optimal EPO action as well as the avoidance of an EPO resistance should be achievable in patients that are treated with rhEPO.